Jung-Hoon Koo

Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease.

The present study was undertaken to further investigate the protective effect of treadmill exercise on the hippocampal proteins associated with neuronal cell death in an aged transgenic (Tg) mice with Alzheimers disease (AD). To address this, Tg mouse model of AD, Tg-NSE/PS2m, which expresses human mutant PS2 in the brain, was chosen. Animals were subjected to treadmill exercise for 12 weeks from 24 months of age. The exercised mice were treadmill run at speed of 12 m/min, 60 min/day, 5 days/week on a 0% gradient for 3 months. Treadmill exercised mice improved cognitive function in water maze test. Treadmill exercised mice significantly reduced the expression of Aβ-42, Cox-2, and caspase-3 in the hippocampus. In parallel, treadmill exercised Tg mice decreased the phosphorylation levels of JNK, p38MAPK and tau (Ser404, Ser202, Thr231), and increased the phosphorylation levels of ERK, PI3K, Akt and GSK-3α/β. In addition, treadmill exercised Tg mice up-regulated the expressions of NGF, BDNF and phospho-CREB, and the expressions of SOD-1, SOD-2 and HSP-70. Treadmill exercised Tg mice up-regulated the expression of Bcl-2, and down-regulated the expressions of cytochrome c and Bax in the hippocampus. The number of TUNEL-positive cells in the hippocampus in mice was significantly decreased after treadmill exercise. Finally, serum TC, insulin, glucose, and corticosterone levels were significantly decreased in the Tg mice after treadmill exercise. As a consequence of such change, Aβ-dependent neuronal cell death in the hippocampus of Tg mice was markedly suppressed following treadmill exercise. These results strongly suggest that treadmill exercise provides a therapeutic potential to inhibit both Aβ-42 and neuronal death pathways. Therefore, treadmill exercise may be beneficial in prevention or treatment of AD.

Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice

Alzheimer’s disease (AD) is characterized by the deposition of aggregated amyloid-beta (Aβ), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of neuronal apoptosis and inflammation by Aβ-induced ER stress to exercise training are not fully understood. Here, we demonstrated that treadmill exercise (TE) prevented PS2 mutation-induced memory impairment and reduced Aβ-42 deposition through the inhibition of β-secretase (BACE-1) and its product, C-99 in cortex and/or hippocampus of aged PS2 mutant mice. We also found that TE down-regulated the expression of GRP78/Bip and PDI proteins and inhibited activation of PERK, eIF2α, ATF6α, sXBP1 and JNK-p38 MAPK as well as activation of CHOP, caspase-12 and caspase-3. Moreover, TE up-regulated the expression of Bcl-2 and down-regulated the expressions of Bax in the hippocampus of aged PS2 mutant mice. Finally, the generation of TNFα and IL-1α and the number of TUNEL-positive cells in the hippocampus of aged PS2 mutant mice was also prevented or decreased by TE. These results showed that TE suppressed the activation of UPR signaling pathways as well as inhibited the apoptotic pathways of the UPR and inflammatory response following Aβ-induced ER stress. Thus, therapeutic strategies that modulate Aβ-induced ER stress through TE could represent a promising approach for the prevention or treatment of AD.

Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson's disease mice

Parkinsons disease (PD) is one of the main degenerative neurological disorders accompanying death of dopaminergic neurons prevalent in aged population. Endurance exercise (EE) has been suggested to confer neurogenesis and mitigate the degree of seriousness of PD. However, underlying molecular mechanisms responsible for exercise-mediated neuroprotection against PD remain largely unknown. Given the relevant interplay between elevated α-synuclein and neuroinflammation in a poor prognosis and vicious progression of PD and anti-inflammatory effects of EE, we hypothesized that EE would reverse motor dysfunction and cell death caused by PD. To this end, we chose a pharmacological model of PD (e.g., chronic injection of neurotoxin MPTP). Young adult male mice (7 weeks old) were randomly divided into three groups: sedentary control (C, n=10), MPTP (M, n=10), and MPTP + endurance exercise (ME, n=10). Our data showed that EE restored motor function impaired by MPTP in parallel with reduced cell death. Strikingly, EE exhibited a significant reduction in α-synuclein protein along with diminished pro-inflammatory cytokines (i.e., TNF-α and IL-1β). Supporting this, EE prevented activation of Toll like receptor 2 (TLR2) downstream signaling cascades such as MyD88, TRAF6 and TAK-1 incurred by in MPTP administration in the striatum. Moreover, EE reestablished tyrosine hydroxylase at levels similar to C group. Taken together, our data suggest that an EE-mediated neuroprotective mechanism against PD underlies anti-neuroinflammation conferred by reduced levels of α-synuclein. Our data provides an important insight into developing a non-pharmacological countermeasure against neuronal degeneration caused by PD.

Treadmill exercise decreases amyloid-β burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer's disease

ABSTRACT Accumulation of amyloid‐&bgr; (A&bgr;) correlates significantly with progressive cognitive deficits, a main symptom of Alzheimers disease (AD). Although treadmill exercise reduces A&bgr; levels, the molecular mechanisms underlying the effects are not fully understood. We hypothesize that treadmill exercise decreases A&bgr; production and alleviates cognitive deficits by activating the non‐amyloidogenic pathway via SIRT‐1 signaling. Treadmill exercise improved cognitive deficits and alleviated neurotoxicity. Most importantly, treadmill exercise increased SIRT‐1 level, which subsequently resulted in increased ADAM‐10 level by down‐regulation of ROCK‐1 and upregulation of RAR&bgr;, ultimately facilitating the non‐amyloidogenic pathway. Treadmill exercise‐induced activation in SIRT‐1 level also elevated PGC‐1&agr; level and reduced BACE‐1 and C‐99 level, resulting in inhibition of the amyloidogenic pathway. Treadmill exercise may thus inhibit A&bgr; production via upregulation of SIRT‐1, which biases amyloid precursor protein processing toward the non‐amyloidogenic pathway. This study provides novel and valuable insight into the molecular mechanisms possibly by which treadmill exercise reduces A&bgr; production. HighlightsTreadmill exercise increased SIRT‐1 levels, resulting in increased ADAM‐10 by downregulating ROCK‐1 and upregulating RAR&bgr;.Treadmill exercise increased PGC‐1&agr; levels, which reduced BACE‐1 and C‐99 expression.Treadmill exercise inhibits A&bgr; production possibly by activating non‐amyloidogenic pathway via SIRT‐1/PGC‐1&agr; signaling.

Treadmill exercise alleviates motor deficits and improves mitochondrial import machinery in an MPTP-induced mouse model of Parkinson's disease.

&NA; Alpha‐synuclein (&agr;‐Syn) accumulation is significantly correlated with motor deficits and mitochondrial dysfunction in Parkinsons disease (PD), but the molecular mechanism underlying its pathogenesis is unclear. In this study, we investigated the effects of treadmill exercise on motor deficits and mitochondrial dysfunction in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of PD. Treadmill exercise inhibited dopaminergic neuron loss by promoting the expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT) and seemed to improve cell survival by reducing &agr;‐Syn expression. Most importantly, treadmill exercise increased expression of the mitochondrial import machinery proteins TOM‐40, TOM‐20, and TIM‐23. This was associated with decreased &agr;‐Syn expression and subsequent upregulation of the mitochondrial proteins COX‐I, COX‐IV, and mtHSP70. Taken together, these results indicate that treadmill exercise may ameliorate motor deficits and improve mitochondrial dysfunction by reducing &agr;‐Syn expression in the MPTP‐induced mouse model of PD. HighlightsTreadmill exercise ameliorates motor deficits in the MPTP‐induced mouse model of PD.Treadmill exercise decreased dopaminergic neurons loss and apoptotic cell death via reduced &agr;‐Syn expression.Treadmill exercise activates the MIM, resulting in improvement of mitochondrial function via reduced &agr;‐Syn expression.

Exercise training and selenium or a combined treatment ameliorates aberrant expression of glucose and lactate metabolic proteins in skeletal muscle in a rodent model of diabetes

Exercise training (ET) and selenium (SEL) were evaluated either individually or in combination (COMBI) for their effects on expression of glucose (AMPK, PGC-1α, GLUT-4) and lactate metabolic proteins (LDH, MCT-1, MCT-4, COX-IV) in heart and skeletal muscles in a rodent model (Goto-Kakisaki, GK) of diabetes. Forty GK rats either remained sedentary (SED), performed ET, received SEL, (5 µmol·kg body wt-1·day-1) or underwent both ET and SEL treatment for 6 wk. ET alone, SEL alone, or COMBI resulted in a significant lowering of lactate, glucose, and insulin levels as well as a reduction in HOMA-IR and AUC for glucose relative to SED. Additionally, ET alone, SEL alone, or COMBI increased glycogen content and citrate synthase (CS) activities in liver and muscles. However, their effects on glycogen content and CS activity were tissue-specific. In particular, ET alone, SEL alone, or COMBI induced upregulation of glucose (AMPK, PGC-1α, GLUT-4) and lactate (LDH, MCT-1, MCT-4, COX-IV) metabolic proteins relative to SED. However, their effects on glucose and lactate metabolic proteins also appeared to be tissue-specific. It seemed that glucose and lactate metabolic protein expression was not further enhanced with COMBI compared to that of ET alone or SEL alone. These data suggest that ET alone or SEL alone or COMBI represent a practical strategy for ameliorating aberrant expression of glucose and lactate metabolic proteins in diabetic GK rats.

Treadmill exercise produces neuroprotective effects in a murine model of Parkinson’s disease by regulating the TLR2/MyD88/NF-κB signaling pathway

Parkinsons disease (PD) is characterized by progressive dopamine depletion and a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Treadmill exercise is a promising non-pharmacological approach for reducing the risk of PD and other neuroinflammatory disorders, such as Alzheimers disease. The goal of this study was to investigate the effects of treadmill exercise on α-synuclein-induced neuroinflammation and neuronal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Eight weeks of treadmill exercise improved motor deficits and reduced α-synuclein expression, a major causative factor of PD-like symptoms, in MPTP mice. Treadmill exercise also down-regulated the expression of toll-like receptor 2 and its associated downstream signaling molecules, including myeloid differentiation factor-88, tumor necrosis factor receptor-associated factor 6, and transforming growth factor-β-activated protein kinase 1. These effects were associated with reduced ionized calcium-binding adapter molecule 1 expression, decreased IκBα and nuclear transcription factor-κB phosphorylation, decreased tumor necrosis factor α and interleukin-1β expression, and decreased NADPH oxidase subunit expression in the SNpc and striatum. Additionally, it promoted the expression of tyrosine hydroxylase and the dopamine transporter, as well as plasma dopamine levels, in MPTP mice; these effects were associated with decreased caspase-3 expression and cleavage, as well as increased Bcl-2 expression in the SNpc. Taken together, our data suggest that treadmill exercise improves MPTP-associated motor deficits by exerting neuroprotective effects in the SNpc and striatum, supporting the notion that treadmill exercise is useful as a non-pharmacological tool for the management of PD.

Neuroprotective Effects of Endurance Exercise against High Fat Diet‐Induced Hippocampal Neuroinflammation

Obesity contributes to systemic inflammation, which is associated with the varied pathogenesis of neurodegenerative diseases. Growing evidence has demonstrated that endurance exercise (EE) mitigates obesity‐induced brain inflammation. However, exercise‐mediated anti‐inflammatory mechanisms remain largely unknown. We investigated how treadmill exercise (TE) reverses obesity‐induced brain inflammation, mainly focusing on toll‐like receptor‐4 (TLR‐4)‐dependent neuroinflammation in the obese rat brain after 20 weeks of a high‐fat diet (HFD). TE in HFD‐fed rats resulted in a significant lowering in the homeostasis model assessment of insulin resistance index, the area under the curve for glucose and abdominal visceral fat, and also improved working memory ability in a passive avoidance task relative to sedentary behaviour in HFD‐fed rats, with the exception of body weight. More importantly, TE revoked the increase in HFD‐induced proinflammatory cytokines (tumour necrosis factor α and interleukin‐1β) and cyclooxygenase‐2, which is in parallel with a reduction in TLR‐4 and its downstream proteins, myeloid differentiation 88 and tumour necrosis factor receptor associated factor 6, and phosphorylation of transforming growth factor β‐activated kinase 1, IkBα and nuclear factor‐κB. Moreover, TE reduced an indicator of microglia activation, ionised calcium‐binding adapter molecule‐1, and also decreased glial fibrillary acidic protein, an indicator of gliosis formed by activated astrocytes in the cerebral cortex and the hippocampal dentate gyrus, compared to HFD‐fed sedentary rats. Finally, EE up‐regulated the expression of anti‐apoptotic protein, Bcl‐2, and suppressed the expression of pro‐apoptotic protein, Bax, in the hippocampus compared to HFD‐fed sedentary rats. Taken together, these data suggest that TE may exert neuroprotective effects as a result of mitigating the production of proinflammatory cytokines by inhibiting the TLR4 signalling pathways. The results of the present study suggest that the unique combination of the beneficial effects of TE on the restoration of the blood profile and the anti‐inflammatory and anti‐apoptotic effects on cognitive function should inspire further investigations into its therapeutic potential for metabolic disorders and neurodegenerative diseases.

Erratum to: Treadmill Exercise Attenuates α-Synuclein Levels by Promoting Mitochondrial Function and Autophagy Possibly via SIRT1 in the Chronic MPTP/P-Induced Mouse Model of Parkinson’s Disease

The original version of this article unfortunately contained mistakes and the authors hereby publishing these corrections. An error occurred in Fig. 8a during the final stages of figure mounting. The published bottom panel of Fig. 8a was inappropriately mounted with the wrong GAPDH Western blot control. The Fig. 8a should be corrected to remove and replace the GAPDHWestern blot control from Fig. 8a.With these, the original article was corrected. The corrected figure is presented on the next page.

Neuroprotective effect of treadmill exercise possibly via regulation of lysosomal degradation molecules in mice with pharmacologically induced Parkinson’s disease

Dysfunction of mitophagy, which is a selective degradation of defective mitochondria for quality control, is known to be implicated in the pathogenesis of Parkinson’s disease (PD). However, how treadmill exercise (TE) regulates mitophagy-related molecules in PD remains to be elucidated. Therefore, we aimed to investigate how TE regulates α-synuclein (α-syn)-induced neurotoxicity and mitophagy-related molecules in the nigro-striatal region of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mice. Our data showed that TE exhibited a significant restoration of tyrosine hydroxylase and motor coordination with suppression of α-syn expression, hallmarks of PD, possibly via up-regulation of lysosomal degradation molecules, LAMP-2 and cathepsin L, with down-regulation of p62, LC3-II/LC3-I ratio, PINK1 and parkin in the substantia nigra of MPTP mice. Therefore, these results suggest that treadmill exercise can be used as a non-invasive intervention to improve the pathological features and maintain a healthier mitochondrial network through appropriate elimination of defective mitochondria in PD.